He graduated with honours from Fort Hare in 1948 and returned to Southern Rhodesia to become a teacher. While pursuing his teaching career he began to make plans for Nyatsime College, a secondary school to be controlled by black officials rather than the government or missionaries. The school, which opened in 1962, provided academic, technical and commercial education for black Africans. He was deeply involved in the liberal politics of Southern Rhodesia during the 1950s and 1960s, but became disillusioned when he came to the conclusion that the white minority in Rhodesia would never accept any multiracial options for the country's government.

During his time at Indiana he began writing historical novels. His book, On Trial for My Country outlined the white man’s conquest of Rhodesia, the struggles of the native people during the conquest, and the clash between Cecil Rhodes and Lobengula, the Matabele king.

Samkange’s best-known work, On Trial for My Country (1966), is a tale told by an old man of the imagined twin trials of Cecil Rhodes and Lobengula, the Ndebele (or Matabele) ruler, who are each tried by their ancestors for their respective parts in obtaining and granting the various concessions that led to the occupation of Matabeleland, Mashonaland and their environs by Rhodes's British South Africa Company in the 1880s and 1890s. Rhodes must convince his ancestors that he has been just and honest in his dealings with the Ndebele king Lobengula and his people, while Lobengula is required to explain to the ancestral spirits just how he had lost the land to the white man. The novel was banned in Rhodesia.